To date more than 100 genetic variants are known to be associated with inflammatory bowel disease (IBD). The majority of these have been identified by genome-wide association studies (GWAS). The individual Genetic Research Centers (GRCs) and the collective NIDDK IBD Genetics Consortium have successfully interacted for the last ten years to lead many of these discoveries. However, despite significant progress it is still unknown how the vast majority of these variants lead to IBD. Answering these questions is critical to advancing our knowledge of IBD pathophysiology. The University of Toronto GRC, led by Dr. Mark Silverberg, has made unique and substantial contributions in this field by virtue of its longstanding clinical and genetics expertise in IBD. Since 2002, Dr. Silverberg has established a very large, comprehensive registry of well characterized, longitudinally followed IBD patients at Mount Sinai Hospital in addition to accompanying biospecimens stored at his laboratory at the Samuel Lunenfeld Research Institute in order to facilitate research in IBD. Utilizing these resources, the UTGRC will advance the understanding of IBD pathophysiology in the following ways: (1) To identify gene expression profiles and pathways that will aid in classifying IBD and in revealing those that are mechanistically important in IBD pathophysiology. This will be accomplished by measuring gene expression profiles in the intestinal tissue of those affected and of healthy controls. (2) To evaluate the interaction between host genetic variation and the intestinal microbiome and determine how these changes affect the phenotypic expression of IBD. This will be accomplished by determining the composition of the microbial flora adherent to the intestinal tissue of those affected and of healthy controls. (3) To continue to work in an interactive fashion with the members of the Consortium to complete the discovery of all genetic variation associated with IBD and to advance our knowledge of the functional biology of such genetic variation such that we will effect change in the outcomes of individuals affected by IBD. This will be accomplished by ongoing clinical patient and biospecimen recruitment and by bringing significant clinical and scientific expertise to the Consortium team. PUBLIC HEALTH RELEVANCE: The University of Toronto Genetic Research Center, working within the NIDDK IBD Genetics Consortium, is proposing a series of projects aimed at fully identifying all of the genetic factors that lead to an inherited predisposition to inflammatory bowl disease (IBD). UTGRC will also investigate how patients with these susceptibility factors actually develop IBD by incorporating studies examining how genes are expressed and the composition of the bacteria in the digestive tract. By understanding these processes the aim is to prevent individuals from developing IBD and to improve the quality of life of those individuals currently affected.